Lysosomal acid lipase-deficient mice: depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span.
Lysosomal acid lipase-deficient mice: depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span.
复制标题
DOI：
--
复制
发表时间：
2001-04
影响因子：
6.5
通讯作者：
H. Du;M. Heur;Duan Ming;G. Grabowski;D. Hui;D. Witte;J. Mishra
中科院分区：
文献类型：
--
作者：
H. Du;M. Heur;Duan Ming;G. Grabowski;D. Hui;D. Witte;J. Mishra
溶酶体酸性脂肪酶（lysosomalacidlipase，LAL）是溶酶体中甘油三酯（triglycerides，TG）和胆固醇酯（cholesterylesters，CE）水解的关键酶。通过基因靶向创建的小鼠模型不产生LAL mRNA、蛋白质或酶活性。lal-/-小鼠在出生时表现正常，存活至成年，并且具有生育能力。在成人肝脏、肾上腺和小肠中观察到TG和CE的大量储存。此处详细描述了该小鼠模型中的年龄依赖性组织和总体进展。虽然lal-/-小鼠可以繁殖产生纯合子窝，但它们在7至8个月大时死亡。lal-/-小鼠出现单个肠系膜淋巴结肿大，其中充满了储存的脂质。在6 - 8月龄时，lal-/-小鼠完全没有腹股沟、肩胛间和腹膜后白色脂肪组织。此外，棕色脂肪组织逐渐丢失。血浆游离脂肪酸水平在lal-/-小鼠中显著高于年龄匹配的lal+/+小鼠，并且血浆胰岛素水平在葡萄糖激发后更高。lal-/-雄性小鼠的能量摄入也更高，尽管年龄匹配的体重与年龄匹配的lal+/+小鼠相比没有显著变化。在病程早期，肝细胞是肝脏中的主要储存细胞;到3;-8个月，储存脂质的枯否细胞逐渐充满肝脏。整个lal-/-小鼠体内巨噬细胞的参与为LAL在细胞胆固醇和脂肪酸代谢、脂肪细胞分化和脂肪动员中的关键未被认识的作用提供了证据。
Lysosomal acid lipase (LAL) is essential for the hydrolysis of triglycerides (TG) and cholesteryl esters (CE) in lysosomes. A mouse model created by gene targeting produces no LAL mRNA, protein, or enzyme activity. The lal-/- mice appear normal at birth, survive into adulthood, and are fertile. Massive storage of TG and CE is observed in adult liver, adrenal glands, and small intestine. The age-dependent tissue and gross progression in this mouse model are detailed here. Although lal-/- mice can be bred to give homozygous litters, they die at ages of 7 to 8 months. The lal-/- mice develop enlargement of a single mesenteric lymph node that is full of stored lipids. At 6;-8 months of age, the lal-/- mice have completely absent inguinal, interscapular, and retroperitoneal white adipose tissue. In addition, brown adipose tissue is progressively lost. The plasma free fatty acid levels are significantly higher in lal-/- mice than age-matched lal+/+ mice, and plasma insulin levels were more elevated upon glucose challenge. Energy intake was also higher in lal-/- male mice, although age-matched body weights were not significantly altered from age-matched lal+/+ mice. Early in the disease course, hepatocytes are the main storage cell in the liver; by 3;-8 months, the lipid-stored Kupffer cells progressively fill the liver. The involvement of macrophages throughout the body of lal-/- mice provide evidence for a critical nonappreciated role of LAL in cellular cholesterol and fatty acid metabolism, adipocyte differentiation, and fat mobilization.